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Archive for the ‘RNA Biology, Cancer and Therapeutics’ Category


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

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Reporter and Curator: Irina Robu, PhD

Monitoring cancer patients and evaluating their response to treatment can sometimes involve invasive procedures, including surgery.

The liquid biopsies have become something of a Holy Grail in cancer treatment among physicians, researchers and companies gambling big on the technology. Liquid biopsies, unlike traditional biopsies involving invasive surgery — rely on an ordinary blood draw. Developments in sequencing the human genome, permitting researchers to detect genetic mutations of cancers, have made the tests conceivable. Some 38 companies in the US alone are working on liquid biopsies by trying to analyze blood for fragments of DNA shed by dying tumor cells.

Premature research on the liquid biopsy has concentrated profoundly on patients with later-stage cancers who have suffered treatments, including chemotherapy, radiation, surgery, immunotherapy or drugs that target molecules involved in the growth, progression and spread of cancer. For cancer patients undergoing treatment, liquid biopsies could spare them some of the painful, expensive and risky tissue tumor biopsies and reduce reliance on CT scans. The tests can rapidly evaluate the efficacy of surgery or other treatment, while old-style biopsies and CT scans can still remain inconclusive as a result of scar tissue near the tumor site.

As recently as a few years ago, the liquid biopsies were hardly used except in research. At the moment, thousands of the tests are being used in clinical practices in the United States and abroad, including at the M.D. Anderson Cancer Center in Houston; the University of California, San Diego; the University of California, San Francisco; the Duke Cancer Institute and several other cancer centers.

With patients for whom physicians cannot get a tissue biopsy, the liquid biopsy could prove a safe and effective alternative that could help determine whether treatment is helping eradicate the cancer. A startup, Miroculus developed a cheap, open source device that can test blood for several types of cancer at once. The platform, called Miriam finds cancer by extracting RNA from blood and spreading it across plates that look at specific type of mRNA. The technology is then hooked up at a smartphone which sends the information to an online database and compares the microRNA found in the patient’s blood to known patterns indicating different type of cancers in the early stage and can reduce unnecessary cancer screenings.

Nevertheless, experts warn that more studies are essential to regulate the accuracy of the test, exactly which cancers it can detect, at what stages and whether it improves care or survival rates.

SOURCE

https://www.fastcompany.com/3037117/a-new-device-can-detect-multiple-types-of-cancer-with-a-single-blood-test

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356857/

Other related articles published in this Open Access Online Scientific Publishing Journal include the following:

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute, Micro and Nanotechnology Lab

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/28/liquid-biopsy-chip-detects-an-array-of-metastatic-cancer-cell-markers-in-blood-rd-worcester-polytechnic-institute-micro-and-nanotechnology-lab/

Liquid Biopsy Assay May Predict Drug Resistance

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/11/06/liquid-biopsy-assay-may-predict-drug-resistance/

One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

https://pharmaceuticalintelligence.com/2017/01/05/one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-biomarkers-rd-wpi

 

 

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Alnylam down as it halts development for RNAi liver disease candidate

The company “presented clinical results from our ALN-AAT program showing potent, dose-dependent, and durable knockdown of the target protein, just as we’ve seen in clinical data presented from all of the other RNAi candidates in our pipeline to date,” said Alnylam’s EVP of R&D and CMO, Dr. Akshay Vaishnaw, in a statement. “In this case, however, we observed a low incidence of asymptomatic, transiently elevated liver enzymes.”

“We plan to advance a follow-on molecule in efforts to optimize the tolerability profile for this program, and we aim to file a CTA for ALN-AAT02 in 2017,” he added. “We remain committed to developing RNAi therapeutics for alpha-1 liver disease, a rare genetic disease with significant unmet need where liver transplantation is the only treatment option beyond supportive care.”

The data presented at the Oligonucleotide Therapeutics Society (OTS) meeting in Montreal was from a 20-patient study with 4 patients in each of 5 ascending dose groups. Each patient received a single subcutaneous dose of ALN-AAT. The trial also included a second part in which 6 patients were randomized 4 to 2 on drug versus placebo. The treatment group received four doses of ALN-AAT, one every 28 days.

SOURCE

CAMBRIDGE, Mass.–(BUSINESS WIRE)–

Alnylam Presents Clinical and Non-Clinical Data Demonstrating Continued RNAi Platform Optimization and Leadership in the Development of RNA-Based Therapeutics at 12th Annual Meeting of the Oligonucleotide Therapeutics Society

September 28, 2016

Alnylam Pharmaceuticals, Inc. (ALNY), the leading RNAi therapeutics company, announced today new clinical and non-clinical research results demonstrating continued RNAi therapeutics platform innovation and optimization, including improved potency, durability, metabolic stability and tolerability with its GalNAc platform, as well as clinical translation across multiple pipeline programs. The research was presented at the 12th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held from September 25 – 28, 2016 in Montreal, Quebec. These data were presented in a series of 10 posters and oral presentations highlighting progress on the Company’s GalNAc platform and its clinical translation. Among the presentations from Alnylam scientists and clinicians, clinical data were presented from the Phase 1/2 study of ALN-AAT, an investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease, also known as alpha-1 liver disease. Results showed that ALN-AAT administration provided potent, dose-dependent, and durable knockdown of serum AAT, although three instances of asymptomatic, transient elevations of liver enzymes were detected in the highest dose groups. As a result, the Company is finalizing selection of a new Development Candidate with plans to rapidly advance this new RNAi therapeutic toward submission of a Clinical Trial Application (CTA) in 2017. In addition, new non-clinical platform data were presented, including an extensive review of data from toxicology studies with GalNAc conjugates.

“We continue to optimize Alnylam’s RNAi therapeutics platform to achieve improved potency, durability, tolerability, and metabolic stability, and we’re pleased to share this progress across 10 presentations at this year’s OTS meeting,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. “We also presented clinical results from our ALN-AAT program showing potent, dose-dependent, and durable knockdown of the target protein, just as we’ve seen in clinical data presented from all of the other RNAi candidates in our pipeline to date. In this case, however, we observed a low incidence of asymptomatic, transiently elevated liver enzymes. We plan to advance a follow-on molecule in efforts to optimize the tolerability profile for this program, and we aim to file a CTA for ALN-AAT02 in 2017. We remain committed to developing RNAi therapeutics for alpha-1 liver disease, a rare genetic disease with significant unmet need where liver transplantation is the only treatment option beyond supportive care.”

New clinical data were presented from the Phase 1/2 trial of ALN-AAT, in which the safety and efficacy of ALN-AAT were evaluated in normal healthy volunteers, and are as of a data transfer date of June 30, 2016. In this study, subjects in Part A (N=20) were enrolled into 5 ascending dose groups (N=4 per group, randomized 3:1 drug:placebo), and received a single subcutaneous dose of ALN-AAT at doses ranging from 0.1 mg/kg to 6 mg/kg. Subjects in Part B (N=6, randomized 4:2 drug:placebo) received 4 doses of ALN-AAT at 1 mg/kg administered every 28 days. ALN-AAT administration resulted in potent, dose-dependent and durable knockdown of serum AAT. A single 6 mg/kg dose of ALN-AAT attained an AAT knockdown of up to 88.9% with a mean maximal knockdown of 83.9 ± 2.6%. The pharmacodynamic effects of ALN-AAT were highly durable, where a single dose at 6 mg/kg maintained mean AAT knockdown of 75.0 ± 1.2% at approximately six months.

ALN-AAT was shown to be generally well tolerated in healthy adult volunteers. There were no drug-related serious adverse events (SAEs), discontinuations due to adverse events (AEs), or injection site reactions reported. Transient, asymptomatic, and dose-dependent increases in liver enzymes were observed in 3 out of 15 healthy volunteers exposed to single doses of ALN-AAT. Since the target patient population for ALN-AAT has established liver disease, Alnylam plans to advance a follow-on molecule targeting a different sequence for further development. Specifically, the Company is finalizing selection of a new Development Candidate – ALN-AAT02 – and plans to rapidly advance this compound towards the clinic, with a planned CTA filing in 2017.

SOURCE

http://finance.yahoo.com/news/alnylam-presents-clinical-non-clinical-200000530.html

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LIVE 9/21 8AM to 10:55 AM Expoloring the Versatility of CRISPR/Cas9 at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14th Annual Discovery on Targettaking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

#BostonDOT16

@BostonDOT

 

COMMENTS BY Stephen J Williams, PhD

EXPLORING THE VERSATILITY OF CRISPR/Cas9

 

8:00 Chairperson’s Opening Remarks

TJ Cradick , Ph.D., Head of Genome Editing, CRISPR Therapeutics

 

@CRISPRTX

 

8:10 Functional Genomics Using CRISPR-Cas9: Technology and Applications

Neville Sanjana, Ph.D., Core Faculty Member, New York Genome Center and Assistant Professor, Department of Biology & Center for Genomics and Systems Biology, New York University

 

CRISPR Cas9 is easier to target to multiple genomic loci; RNA specifies DNA targeting; with zinc finger nucleases or TALEEN in the protein specifies DNA targeting

 

  • This feature of crisper allows you to make a quick big and cheap array of a GENOME SCALE Crisper Knock out (GeCKO) screening library
  • How do you scale up the sgRNA for whole genome?; for all genes in RefSeq, identify consitutive exons using RNA-sequencing data from 16 primary human tissue (alot of genes end with ‘gg’) changing the bases on 3’ side negates crisper system but changing on 5’ then crisper works fine
  • Rank sequences to be specific for target
  • Cloned array into lentiviral and put in selectable markers
  • GeCKO displays high consistency betweens reagents for the same gene versus siRNA; GeCKO has high screening sensitivity
  • 98% of genome is noncoding so what about making a library for intronic regions (miRNA, promoter regions?)
  • So you design the sgRNA library by taking 100kb of gene-adjacent regions
  • They looked at CUL3; (data will soon be published in Science)
  • Do a transcription CHIP to verify the lack of binding of transcription factor of interest
  • Can also target histone marks on promoter and enhancer elements
  • NYU wants to explore this noncoding screens
  • sanjanalab.org

 

@nyuniversity

 

8:40 Therapeutic Gene Editing With CRISPR/Cas9

TJ Cradick , Ph.D., Head of Genome Editing, CRISPR Therapeutics

 

NEHJ is down and dirty repair of single nonhomologous end but when have two breaks the NEHJ repair can introduce the inversions or deletions

 

    • High-throughput screens are fine but can limit your view of genomic context; genome searches pick unique sites so use bioinformatic programs  to design specific guide Rna
    • Bioinformatic directed, genome wide, functional screens
    • Compared COSMID and CCTOP; 320 COSMID off-target sites, 333 CCtop off target
    • Young lab GUIDESeq program genome wide assay useful to design guides
    • If shorten guide may improve specificity; also sometime better sensitivity if lengthen guide

 

  • Manufacturing of autologous gene corrected product ex vivo gene correction (Vertex, Bayer, are partners in this)

 

 

They need to use a clones from multiple microarrays before using the GUidESeq but GUIDEseq is better for REMOVING the off targets than actually producing the sgRNA library you want (seems the methods for library development are not fully advanced to do this)

 

The score sometimes for the sgRNA design programs do not always give the best result because some sgRNAs are genome context dependent

9:10 Towards Combinatorial Drug Discovery: Mining Heterogeneous Phenotypes from Large Scale RNAi/Drug Perturbations

Arvind Rao, Ph.D., Assistant Professor, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center

 

Bioinformatics in CRISPR screens:  they looked at image analysis of light microscopy of breast cancer cells and looked for phenotypic changes

 

  • Then they modeled in a small pilot and then used the algorithm for 20,000 images (made morphometric measurements)
  • Can formulate training statistical algorithms to make a decision tree how you classify data points
  • Although their algorithms worked well there was also human input from scientists

Aggregate ranking of hits programs available on web like LINKS

 

@MDAndersonNews

 

10:25 CRISPR in Stem Cell Models of Eye Disease

Alexander Bassuk, M.D., Ph.D., Associate Professor of Pediatrics, Department of Molecular and Cellular Biology, University of Iowa

 

Blind athlete Michael Stone, biathlete, had eye disease since teenager helped fund and start the clinical trial for Starbardt disease; had one bad copy of ABCA4, heterozygous (inheritable in Ahkenazi Jewish) – a recessive inheritable mutation with juvenile macular degeneration

  • Also had another male in family with disease but he had another mutation in the RPGR gene
  • December 2015 paper Precision Medicine: Genetic Repair of retinitis pigmentosa in patient derived stem cells
  • They were able to correct the iPSCs in the RPGR gene derived from patient however low efficiency of repair, scarless repair, leaves changes in DNA, need clinical grade iPSCs, and need a humanized model of RPGR

@uiowa

10:55 CRISPR in Mouse Models of Eye Disease

Vinit Mahajan, M.D., Ph.D., Assistant Professor of Ophthalmology and Visual Sciences, University of Iowa College of Medicine

  • degeneration of the retina will see brown spots, the macula will often be preserved but retinal cells damaged but with RPGR have problems with peripheral vision, retinitis pigmentosa get tunnel vision with no peripheral vision (a mouse model of PDE6 Knockout recapitulates this phenotype)
  • the PDE6 is linked to the rhodopsin GTP pathway
  • rd1 -/- mouse has something that looks like retinal pigmentosa; has mutant PDE6; is actually a nonsense mutation in rd1 so they tried a crisper to fix in mice
  • with crisper fix of rd1 nonsense mutation the optic nerve looked comparible to normal and the retina structure restored
  • photoreceptors layers- some recovery but not complete
  • sequence results show the DNA is a mosaic so not correcting 100% but only 35% but stil leads to a phenotypic recovery; NHEJ was about 12% to 25% with large deletions
  • histology is restored in crspr repaired mice
  • CRSPR off target effects: WGS and analyze for variants SNV/indels, also looked at on target and off target regions; there were no off target SNVs indels while variants that did not pass quality control screening not a single SNV
  • Rhodopsin mutation accounts for a large % of patients (RhoD190N)
  • injection of gene therapy vectors: AAV vector carrying CRSPR and cas9 repair templates

CAPN mouse models

  • family in Iowa have dominant mutation in CAPN5; retinal degenerates
  • used CRSPR to generate mouse model with mutation in CAPN5 similar to family mutation
  • compared to other transgenic methods CRSPR is faster to produce a mouse model

To Follow LIVE CONFERENCE COVERAGE PLEASE FOLLOW ON TWITTER USING

Meeting #: #BostonDOT16

Meeting @: @BostonDOT

 

Overall good meeting #s:

#personalizedmedicine

#innovation

#cancer

#immunology

#immunooncology

#pharmanews

#CRSPR

#geneediting

#crisper

#biotech

 

AND FOLLOW these @

@pharma_BI

@AVIVA_1950

@BiotechNews

@CHI

@FierceBiotech

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Milestones in Physiology & Discoveries in Medicine and Genomics: Request for Book Review Writing on Amazon.com


physiology-cover-seriese-vol-3individualsaddlebrown-page2

Milestones in Physiology

Discoveries in Medicine, Genomics and Therapeutics

Patient-centric Perspective 

http://www.amazon.com/dp/B019VH97LU 

2015

 

 

Author, Curator and Editor

Larry H Bernstein, MD, FCAP

Chief Scientific Officer

Leaders in Pharmaceutical Business Intelligence

Larry.bernstein@gmail.com

Preface

Introduction 

Chapter 1: Evolution of the Foundation for Diagnostics and Pharmaceuticals Industries

1.1  Outline of Medical Discoveries between 1880 and 1980

1.2 The History of Infectious Diseases and Epidemiology in the late 19th and 20th Century

1.3 The Classification of Microbiota

1.4 Selected Contributions to Chemistry from 1880 to 1980

1.5 The Evolution of Clinical Chemistry in the 20th Century

1.6 Milestones in the Evolution of Diagnostics in the US HealthCare System: 1920s to Pre-Genomics

 

Chapter 2. The search for the evolution of function of proteins, enzymes and metal catalysts in life processes

2.1 The life and work of Allan Wilson
2.2  The  evolution of myoglobin and hemoglobin
2.3  More complexity in proteins evolution
2.4  Life on earth is traced to oxygen binding
2.5  The colors of life function
2.6  The colors of respiration and electron transport
2.7  Highlights of a green evolution

 

Chapter 3. Evolution of New Relationships in Neuroendocrine States
3.1 Pituitary endocrine axis
3.2 Thyroid function
3.3 Sex hormones
3.4 Adrenal Cortex
3.5 Pancreatic Islets
3.6 Parathyroids
3.7 Gastointestinal hormones
3.8 Endocrine action on midbrain
3.9 Neural activity regulating endocrine response

3.10 Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

 

Chapter 4.  Problems of the Circulation, Altitude, and Immunity

4.1 Innervation of Heart and Heart Rate
4.2 Action of hormones on the circulation
4.3 Allogeneic Transfusion Reactions
4.4 Graft-versus Host reaction
4.5 Unique problems of perinatal period
4.6. High altitude sickness
4.7 Deep water adaptation
4.8 Heart-Lung-and Kidney
4.9 Acute Lung Injury

4.10 Reconstruction of Life Processes requires both Genomics and Metabolomics to explain Phenotypes and Phylogenetics

 

Chapter 5. Problems of Diets and Lifestyle Changes

5.1 Anorexia nervosa
5.2 Voluntary and Involuntary S-insufficiency
5.3 Diarrheas – bacterial and nonbacterial
5.4 Gluten-free diets
5.5 Diet and cholesterol
5.6 Diet and Type 2 diabetes mellitus
5.7 Diet and exercise
5.8 Anxiety and quality of Life
5.9 Nutritional Supplements

 

Chapter 6. Advances in Genomics, Therapeutics and Pharmacogenomics

6.1 Natural Products Chemistry

6.2 The Challenge of Antimicrobial Resistance

6.3 Viruses, Vaccines and immunotherapy

6.4 Genomics and Metabolomics Advances in Cancer

6.5 Proteomics – Protein Interaction

6.6 Pharmacogenomics

6.7 Biomarker Guided Therapy

6.8 The Emergence of a Pharmaceutical Industry in the 20th Century: Diagnostics Industry and Drug Development in the Genomics Era: Mid 80s to Present

6.09 The Union of Biomarkers and Drug Development

6.10 Proteomics and Biomarker Discovery

6.11 Epigenomics and Companion Diagnostics

 

Chapter  7

Integration of Physiology, Genomics and Pharmacotherapy

7.1 Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

7.2 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

7.3 Diagnostics and Biomarkers: Novel Genomics Industry Trends vs Present Market Conditions and Historical Scientific Leaders Memoirs

7.4 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

7.5 Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

7.6 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

7.7 Neuroprotective Therapies: Pharmacogenomics vs Psychotropic drugs and Cholinesterase Inhibitors

7.8 Metabolite Identification Combining Genetic and Metabolic Information: Genetic association links unknown metabolites to functionally related genes

7.9 Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

7.10 Biosimilars: Intellectual Property Creation and Protection by Pioneer and by

7.11 Demonstrate Biosimilarity: New FDA Biosimilar Guidelines

 

Chapter 7.  Biopharma Today

8.1 A Great University engaged in Drug Discovery: University of Pittsburgh

8.2 Introduction – The Evolution of Cancer Therapy and Cancer Research: How We Got Here?

8.3 Predicting Tumor Response, Progression, and Time to Recurrence

8.4 Targeting Untargetable Proto-Oncogenes

8.5 Innovation: Drug Discovery, Medical Devices and Digital Health

8.6 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

8.7 Nanotechnology and Ocular Drug Delivery: Part I

8.8 Transdermal drug delivery (TDD) system and nanotechnology: Part II

8.9 The Delicate Connection: IDO (Indolamine 2, 3 dehydrogenase) and Cancer Immunology

8.10 Natural Drug Target Discovery and Translational Medicine in Human Microbiome

8.11 From Genomics of Microorganisms to Translational Medicine

8.12 Confined Indolamine 2, 3 dioxygenase (IDO) Controls the Homeostasis of Immune Responses for Good and Bad

 

Chapter 9. BioPharma – Future Trends

9.1 Artificial Intelligence Versus the Scientist: Who Will Win?

9.2 The Vibrant Philly Biotech Scene: Focus on KannaLife Sciences and the Discipline and Potential of Pharmacognosy

9.3 The Vibrant Philly Biotech Scene: Focus on Computer-Aided Drug Design and Gfree Bio, LLC

9.4 Heroes in Medical Research: The Postdoctoral Fellow

9.5 NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

9.6 1st Pitch Life Science- Philadelphia- What VCs Really Think of your Pitch

9.7 Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

9.8 Heroes in Medical Research: Green Fluorescent Protein and the Rough Road in Science

9.9 Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

9.10 The SCID Pig II: Researchers Develop Another SCID Pig, And Another Great Model For Cancer Research

Epilogue

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On its way for an IPO: mRNA platform, Moderna, Immune Oncology is recruiting 100 new Life Scientists in Cambridge, MA

Curator: Aviva Lev-Ari, PhD, RN

 

Deals:

Moderna has now raised $1.9 billion from investors like AstraZeneca – 9% stack [AstraZeneca’s Pascal Soriot helped get that all started with a whopping $240 million upfront in its 2013 deal, which was tied to $180 million in milestones.], with another $230 million on the table from grants. In addition to the financing announcement this morning, Moderna is also unveiling a pact to develop a new Zika vaccine, with BARDA putting up $8 million to get the program started while offering an option on $117 million more to get through a successful development program.

Novel Strategy in Biotech:

in biotech. Instead of grabbing one or two new drugs and setting out to gather proof-of-concept data to help establish its scientific credibility, the company has harvested a huge windfall of cash and built a large organization before even entering the clinic. And it did that without turning to an IPO.

Pipeline include:

  • The deal with AstraZeneca covers new drugs for cardiovascular, metabolic and renal diseases as well as cancer.
  • partners filed a European application to start a Phase I study of AZD8601, an investigational mRNA-based therapy that encodes for vascular endothelial growth factor-A (VEGF-A)
  • Moderna CEO spelled out plans to get the first 6 new drugs in the clinic by the end of 2016.
  • The first human study was arranged for the infectious disease drug mRNA 1440, which began an early stage study in 2015.
  • Moderna built up a range of big preclinical partnerships.
  • CEO Bancel says the number of drugs in development has swelled to 11, with the first set of data slated to be released in 2017.
  • Moderna also plans to add about 10 drugs to the clinic by next summer,

 

SOURCES

UPDATED: Booming Moderna is raising $600M while ramping up manufacturing and clinical studies

$1.9B in: Moderna blueprints $100M facility, plans to double the pipeline after a $474M megaround

http://endpts.com/moderna-blueprints-100m-facility-plans-to-double-the-pipeline-after-a-474m-megaround/?utm_source=Sailthru&utm_medium=email&utm_campaign=Issue:%202016-09-07%20BioPharma%20Dive%20%5Bissue:7155%5D&utm_term=BioPharma%20Dive

 

Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Curator & Reporter: Stephen J. Williams, PhD – August 11, 2016

https://pharmaceuticalintelligence.com/2016/08/11/moderna-therapeutics-deal-with-merck-are-personalized-vaccines-here/

 

at #JPM16 – Moderna Therapeutics turns away an extra $200 million: with AstraZeneca (collaboration) & with Merck ($100 million investment)

Reporter: Aviva Lev-Ari, PhD, RN – January 13, 2016

https://pharmaceuticalintelligence.com/2016/01/13/at-jpm16-moderna-therapeutics-turns-away-an-extra-200-million-with-astrazeneca-collaboration-with-merck-100-million-investment/

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Moderna Therapeutics Deal with Merck: Are Personalized Vaccines here?

Curator & Reporter: Stephen J. Williams, Ph.D.

Take aways:

  • RNA based vaccines are a cost-effective method of developing and manufacturing a personalized cancer vaccine strategy; traditional vaccine methodology has not been met with much success as a cancer therapeutic
  • Most of the older RNA vaccine technology depended on isolated dendritic cells or T cell populations and ex-vivo treatment with RNA vaccine, HOWEVER, Moderna has developed a technology that circumvents the need for ex-vivo vaccination
  • There are multiple companies involved in this new RNA strategy (Moderna, Caperna {now Moderna}, CureVac, Biontech)

From BusinessWire at http://www.businesswire.com/news/home/20160629005446/en/Merck-Moderna-Announce-Strategic-Collaboration-Advance-mRNA-Based

Merck and Moderna Announce Strategic Collaboration to Advance Novel mRNA-Based Personalized Cancer Vaccines with KEYTRUDA®(pembrolizumab) for the Treatment of Multiple Types of Cancer

Collaboration Combines Merck’s Leadership in Immuno-Oncology with Moderna’s Pioneering mRNA Vaccine Technology and Rapid Cycle Time, Small-Batch GMP Manufacturing Capabilities

KENILWORTH, N.J. & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Merck (NYSE:MRK), known as MSD outside the United States and Canada, and Moderna Therapeutics today announced a strategic collaboration and license agreement to develop and commercialize novel messenger RNA (mRNA)-based personalized cancer vaccines. The collaboration will combine Merck’s established leadership in immuno-oncology with Moderna’s pioneering mRNA vaccine technology and GMP manufacturing capabilities to advance individually tailored cancer vaccines for patients across a spectrum of cancers.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients”

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Moderna and Merck will develop personalized cancer vaccines that utilize Moderna’s mRNA vaccine technology to encode a patient’s specific neoantigens, unique mutations present in that specific patient’s tumor. When injected into a patient, the vaccine will be designed to elicit a specific immune response that will recognize and destroy cancer cells. The companies believe that the mRNA-based personalized cancer vaccines’ ability to specifically activate an individual patient’s immune system has the potential to be synergistic with checkpoint inhibitor therapies, including Merck’s anti-PD-1 therapy, KEYTRUDA® (pembrolizumab). In addition, Moderna has developed a rapid cycle time, small-batch manufacturing technique that will uniquely allow the company to supply vaccines tailored to individual patients within weeks.

Under the terms of the agreement, Merck will make an upfront cash payment to Moderna of $200 million, which Moderna will use to lead all research and development efforts through proof of concept. The development program will entail multiple studies in several types of cancer and include the evaluation of mRNA-based personalized cancer vaccines in combination with Merck’s KEYTRUDA® (pembrolizumab). Moderna will also utilize the upfront payment to fund a portion of the build-out of a GMP manufacturing facility in suburban Boston for the purpose of personalized cancer vaccine manufacturing.

Following human proof of concept studies, Merck has the right to elect to make an additional undisclosed payment to Moderna. If exercised, the two companies will then equally share cost and profits under a worldwide collaboration for the development of personalized cancer vaccines. Moderna will have the right to elect to co-promote the personalized cancer vaccines in the U.S. The agreement entails exclusivity around combinations with KEYTRUDA. Moderna and Merck will each have the ability to combine mRNA-based personalized cancer vaccines with other (non-PD-1) agents.

Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients,” said Dr. Roger Perlmutter, President, Merck Research Laboratories. “While the area of personalized cancer vaccine research has faced challenges in the past, there have been many recent advances, and we believe that working with Moderna to combine an immuno-oncology approach, using KEYTRUDA, with mRNA-based personalized cancer vaccines may have the potential to transform the treatment of cancer.”

“Our team has made significant progress since beginning our work in personalized cancer vaccines just last year. Through this collaboration with Merck, we are now well-positioned to accelerate research and development with a goal of entering the clinic in 2017, as well as to apply our unique GMP manufacturing capabilities to support the rapid production of these highly individualized vaccines,” said Stéphane Bancel, chief executive officer of Moderna. “We value our continued collaboration with Merck, and we look forward to working together to harness the potential of personalized cancer vaccines and immuno-oncology to bring a new treatment paradigm to patients.”

Merck and Moderna have an existing collaboration and license agreement focused on the discovery and development of mRNA-based infectious disease vaccines and passive immunity treatments. Moderna is also advancing its own pipeline of infectious disease vaccine candidates and currently has two phase 1 studies underway in Europe and the U.S.

About Moderna Therapeutics

Moderna is a clinical stage pioneer of messenger RNA Therapeutics™, an entirely new in vivo drug technology that produces human proteins, antibodies and entirely novel protein constructs inside patient cells, which are in turn secreted or active intracellularly. This breakthrough platform addresses currently undruggable targets and offers a potentially superior alternative to existing drug modalities for a wide range of diseases and conditions. Moderna is developing and plans to commercialize its innovative mRNA drugs through its own ventures and its strategic relationships with established pharmaceutical and biotech companies. Its current ventures are:

  • Onkaido, focused on oncology,
  • Valera, focused on infectious diseases,
  • Elpidera, focused on rare diseases, and
  • Caperna, focused on personalized cancer vaccines.

Cambridge-based Moderna is privately held and currently has strategic agreements with AstraZeneca, Alexion Pharmaceuticals and Merck. To learn more, visit www.modernatx.com.

From the Moderna Therapeutics Website

Our mRNA Platform

At Moderna, we are pioneering the development of a new class of drugs made of messenger RNA (mRNA). This novel drug platform builds on the discovery that modified mRNA can direct the body’s cellular machinery to produce nearly any protein of interest, from native proteins to antibodies and other entirely novel protein constructs that can have therapeutic activity inside and outside of cells.

Our efforts are helping Moderna and the industry to flatten the mRNA learning curve across the full breadth of competencies needed to drive the platform forward, including chemistry, mRNA biology, formulation, process development, automation and high-throughput production, quality, and Good Manufacturing Practice (GMP) manufacturing.

Drug Modalities

Building from our mRNA core expression platform, we have created a new scale of drug discovery and development that enables a series of new drug modalities. Each modality represents a distinct approach to using the mRNA platform to encode proteins that achieve a therapeutic benefit, enabling us to develop numerous drug candidates across a wide array of therapeutic areas.

Vaccines

Vaccines are substances that teach the immune system to rapidly recognize and destroy invading pathogens such as bacteria or viruses, preparing the body’s adaptive immunity for future exposure to the pathogen. Historically, vaccines have introduced immune-activating markers from pathogens into the body. Conversely, Moderna is developing mRNA-based vaccines that enable the body to produce and present immunogenic proteins to the immune system.

Moderna is also developing mRNA-based personalized cancer vaccines to prime the immune system to recognize cancer cells and mount a strong, tailored response to each individual patient’s cancer. Moderna’s technology allows for a rapid turn-around time in production of these unique mRNA vaccines.

Intracellular/Transmembrane

Many diseases are caused by defects in proteins that function inside cells. Existing methods of protein-based therapy do not allow for proteins to reach the intracellular space, and as such are unable to replace the defective, disease-causing proteins within cells. Moderna’s platform allows for the development of mRNA therapies that can stimulate production of intracellular proteins as well as transmembrane proteins. This could potentially lead to a novel approach to treating a vast array of rare genetic and other diseases caused by intracellular protein defects.

Intratumoral

Many targets for the treatment of cancer have been identified but their therapeutic potential has been limited by either the inability to access these targets, or by systemic toxicities. Moderna’s platform allows for localized expression of therapeutic proteins within the tumor microenvironment.

Secreted antibodies

Antibodies are secreted proteins that bind to and inhibit specific targets. Moderna’s platform has the potential to stimulate the body’s own cells to produce specific antibodies that can bind to cellular targets.

Secreted proteins

Proteins are large, complex molecules that have many critical functions both inside and outside of cells. Moderna’s platform stimulates cells to produce and secrete proteins that can have a therapeutic benefit through systemic exposure.

Moderna is comprised of four smaller companies, the following three are involved in their personalized immunotherapy and cancer vaccine strategy

Caperna LLC

Caperna

Caperna LLC is the fourth Moderna venture company — formed, funded and wholly-owned by Moderna — and focused exclusively on the advancement of personalized cancer vaccines.

Caperna will apply Moderna’s mRNA vaccine technology to the field of cancer vaccines, building on advances in recent years in cancer immunotherapy. Utilizing Moderna’s demonstrated engineering and process capability to synthesize over 1,000 unique novel mRNA’s per month in Moderna’s, automated, in-house productions systems. This provides the basis for a vision of rapid turnaround times that will allow Caperna’s personalized cancer vaccine, customized after tumor biopsy and sequencing to code for specific neoantigens in patients’ tumors, to be used to treat patients with aggressive tumors and high unmet need (rather than those with less aggressive tumors which can’t wait for prolonged turnaround times). Caperna will develop its personalized cancer vaccines in combination with checkpoint inhibitors that unleash the immune system and other cancer immunotherapies.

Corporate Facts

  • President: Tal Zaks, M.D., Ph.D.
  • Head of Research: Nicholas Valiante, Ph.D.
  • Head of Operations: Ted Ashburn, M.D., Ph.D.
  • Headquarters: 500 Technology Square, Cambridge, Mass.
  • Phone: 617-714-6500
  • Website: Caperna.com

 

Onkaido

Onkaido

Onkaido Therapeutics is the first Moderna venture company – formed, funded and wholly-owned by Moderna. Onkaido is focused exclusively on developing mRNA-based oncology treatments for currently undruggable targets or as a superior alternative to existing drug modalities. Onkaido is leveraging all of the tools and modalities developed at Moderna, with plans to rapidly turn mRNA science into truly novel cancer therapies that can make a real difference for patients.

Onkaido is currently focused on three therapeutic areas of oncology drug discovery and development: immuno-oncology, hepatocellular carcinoma (liver cancer) and myeloid malignancies – with programs investigating multiple targets and therapies simultaneously. Onkaido scientists are also exploring the power of mRNA technology in precision cancer pharmacology – researching areas such as tumor biology, targeting and gene silencing, driving the science toward the delivery of truly personalized cancer treatment.

Corporate Facts

  • President: Stephen Kelsey, M.D.
  • Headquarters: 500 Technology Square, Cambridge, Mass.
  • Phone: 617-714-6500
  • Website: Onkaido.com

 

Valera

Valera

Valera LLC is the second Moderna venture company — formed, funded and wholly-owned by Moderna — and focused exclusively on the advancement of vaccines and therapeutics for the prevention and treatment of viral, bacterial and parasitic infectious diseases.

The vaccines work of Valera builds on a body of preclinical research at Moderna showing the ability of modified mRNA to express viral antigens in vivo and to induce robust immune responses. Valera’s therapeutic passive immunity programs will expand on Moderna’s research using mRNA to express antibodies that bind to viral and other targets. The robust data from these programs across a range of preclinical infectious disease models, together with the inherent, rapid turn-around time in creating novel mRNA constructs, provide Valera with a potentially powerful and versatile new platform for the creation of a broad array of vaccines and passive immunity therapies.

Corporate Facts

  • President: Michael Watson, MB ChB, MRCP, AFPM
  • Chief Scientific OfficerGiuseppe Ciaramella, Ph.D.
  • Interim Chief Medical OfficerTal Zaks, M.D., Ph.D.
  • Headquarters: 500 Technology Square, Cambridge, Mass.
  • Phone: 617-714-6500
  • Website: Valeratx.com

And from http://endpts.com/neoantigens-beckon-merck-into-a-200m-cancer-collaboration-with-moderna/

Neoantigens beckon Merck into a $200M cancer collaboration with Moderna


Now that Galena has added fresh evidence that first-gen cancer vaccines make for a poor R&D program, Merck is betting $200 million upfront that the next-gen neoantigen approach to personalized cancer vaccines can succeed where all else has failed.

Merck is tying up with the mRNA specialists at Cambridge, MA-based Moderna, which has inked a long lineup of marquee partnerships. The big idea here is that each person’s cancer cells present unique “neoantigens” that can be used to tailor a cancer vaccine for each patient.

That’s a radical idea that has gained considerable steam in recent months, with Gritstone and Neon Therapeutics — paired now with Bristol-Myers on Opdivo — rounding up significant venture cash. Biotech billionaire Patrick Soon-Shiong has also jumped into the game, including it in its growing slate of cancer R&D work in a group of startups.

Moderna says it has already set up a manufacturing system that can be used to create these personalized vaccines in a matter of weeks. And Merck will use the partnership to advance new combination therapies that include its checkpoint inhibitor Keytruda.

The way the deal works, Moderna notes in its statement, is that Merck can step up after it sees some evidence in humans that the tech is working as planned. After human proof-of-concept, if Merck wants to opt in they can pay a significant milestone and then both companies can share the cost on Phase III and commercializations, profiting equally.Moderna CEO Stéphane Bancel says they can jump into the clinic next year.

The deal marks another rare pact by Merck R&D chief Roger Perlmutter, who’s been carefully focused on making Keytruda a foundation franchise that can sustain the company for years to come. While Merck has been a couple of steps behind Bristol-Myers in gaining market share, Perlmutter’s not settling for a second place finish.

“Combining immunotherapy with vaccine technology may be a new path toward improving outcomes for patients,” said Perlmutter, president, Merck Research Laboratories. “While the area of personalized cancer vaccine research has faced challenges in the past, there have been many recent advances, and we believe that working with Moderna to combine an immuno-oncology approach, using KEYTRUDA, with mRNA-based personalized cancer vaccines may have the potential to transform the treatment of cancer.”

From FierceBiotech on failure of Galena’s breast cancer vaccine trial

Galena plummets into microcap territory on Phase III breast cancer vaccine trial halt

Immunother Cancer. 2015; 3: 26.
Published online 2015 Jun 16. doi:  10.1186/s40425-015-0068-y
PMCID: PMC4468959

Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study

Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
CureVac GmbH, Paul-Ehrlich-Str. 15, Tuebingen, 72076 Germany
Charité University Hospital Berlin, Berlin, Germany
University Hospital Freiburg, Freiburg, Germany
Universitäty Hospital Essen, Essen, Germany
San Raffaele Scientific Institute, Milan, Italy
University Hospital of the Johannes-Gutenberg-University Mainz, Mainz, Germany
Ortenau Klinikum Offenburg-Gengenbach, Offenburg, Germany
University Hospital Göttingen, Göttingen/University Hospital Mannheim, Mannheim, Germany
University Hospital Schleswig-Holstein Campus Luebeck, Luebeck, Germany
Rippin-Consulting, Solingen, Germany
University Hospital Tuebingen, Tuebingen, Germany
Hubert Kübler, ed.nehcneum-ut.zrl@relbeuK.H.
corresponding authorCorresponding author.
#Contributed equally.

Abstract

Background

CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer.

Methods

44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3–6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17.

Results

The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a].

Conclusions

The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic.

The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach.

SOURCE

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468959/

Other articles in the Open Access Journal on Cancer Vaccines Include:

Cancer Vaccines: Targeting Cancer Genes for Immunotherapy – A Conference by Keystone Symposia on Molecular and Cellular Biology

AACR2016 – Cancer immunotherapy

Aduro Biotech Phase II Pancreatic Cancer Trial CRS-207 plus cancer vaccine GVAX Fails

Cases in Biotech Entrepreneurship: Selective Start Ups in 2016

at #JPM16 – Moderna Therapeutics turns away an extra $200 million: with AstraZeneca (collaboration) & with Merck ($100 million investment)

 

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